LAMATER

Lamater250 mg Tablets

Each tablet contains terbinafine hydrochloride, equivalent to 250mg terbinafine.

For a full list of excipients, see section 6.1.

Tablet

Lamater250 mg Tablets are white to off-white tablets with a T on one side and score line on the reverse. The tablet can be divided into equal halves.

Fungal infections of the skin and nails caused by Trichophyton (eg. T. rubrum, T.mentagrophytes, T. verrucosum, T. violaceum), Microsporum canis and Epidermophyton floccosum.

• Oral terbinafine is indicated in the treatment of ringworm (tinea corporis, tinea cruris and tinea pedis) where oral therapy is considered appropriate due to the site, severity or extent of the infection.
• Oral terbinafine is indicated in the treatment of onychomycosis.

Consideration should be given to official guidance on the appropriate use of antifungal agents.

Adults

250mg once daily.

The duration of treatment varies according to the indication and the severity of the infection.

Skin infections

Likely durations of treatment are as follows:

Tinea pedis (interdigital, plantar/moccasin type): two to six weeks

Tinea corporis: four weeks

Tinea cruris: two to four weeks

Onychomycosis

The duration of treatment for most patients is between six weeks and three months. Treatment periods of less than three months can be anticipated in patients with fingernail infection, toenail infection other than of the big toe, or patients of younger age. In the treatment of toenail infections, three months is usually sufficient although a few patients may require treatment of six months or longer. Poor nail outgrowth during the first weeks of treatment may enable identification of those patients in whom longer therapy is required.

Complete resolution of the signs and symptoms of infection may not occur until several weeks after mycological cure.

Additional information on special population:

Liver impairment

Lamater tablets are contraindicated for patients with chronic or active hepatic disease (see sections 4.3 Contraindications and 4.4 Special warnings and precautions for use).

Renal impairment

Use of Lamater tablets has not been adequately studied in patients with renal impairment and is therefore not recommended in this population (see section 4.4 Special warnings and precautions for use and section 5.2 Pharmacokinetic properties).

Paediatric population

Data are limited so use is not recommended.

Elderly

There is no evidence to suggest that elderly patients (aged 65 years or above) require different dosages or experience side-effects different to those of younger patients. The possibility of impairment of liver or kidney function should be considered in this age group (see Section 4.4 Special warnings and precautions for use).

Method of administration

The scored tablets to be taken orally with water. They should preferably be taken at the same time each day and can be taken on an empty stomach or after a meal.

Known hypersensitivity to terbinafine or to any of the excipients listed in section 6.1.

Chronic or active hepatic disease.

Liver function

Lamater tablets are contraindicated for patients with chronic or active hepatic disease. Before prescribing Lamater Tablets, liver function test should be performed and any pre-existing liver disease should be assessed. Hepatotoxicity may occur in patients with and without pre-existing hepatic disease therefore periodic monitoring (after 4-6 weeks of treatment) of liver function test is recommended. Lamater tablets should be immediately discontinued in case of elevation of liver function test. Very rare cases of serious hepatic failure (some with a fatal outcome, or requiring hepatic transplant) have been reported in patients treated with Lamater tablets. In the majority of hepatic failure cases the patients had serious underlying systemic conditions and a causal association with the intake of Lamater tablets was uncertain (see sections 4.3 Contraindication and 4.8 Undesirable effects).

Patients prescribed Lamater tablets should be warned to report immediately any signs or symptoms suggestive of liver dysfunction such as pruritus, of unexplained persistent nausea, decreased appetite, anorexia, fatigue, vomiting, right upper abdominal pain, or jaundice, dark urine or pale faeces to their doctor. Patients with these symptoms should discontinue taking oral terbinafine and the patient's hepatic function should be immediately evaluated.

Single dose pharmacokinetic studies in patients with pre-existing liver disease have shown that the clearance of terbinafine may be reduced by about 50%.

Dermatological effects

Serious skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms)) have been very rarely reported in patients taking Lamater tablets. If progressive skin rash occurs, Lamater tablets treatment should be discontinued.

Lamater should be used with caution in patients with pre-existing psoriasis, as very rare cases of exacerbation of psoriasis have been reported.

Haematological effects

Very rare cases of blood disorders (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported in patients treated with Lamater tablets. Aetiology of any blood disorders that occur in patients treated with Lamater tablets should be evaluated and consideration should be given for a possible change in medication regimen, including discontinuation of treatment with Lamater tablets.

Renal function

In patients with renal impairment (creatinine clearance less than 50 mL/min or serum

creatinine of more than 300 micro mol/L) the use of Lamater tablets has not been adequately studied, and therefore, is not recommended (see section 5.2 Pharmacokinetic properties).

Other

Lamater should be used with caution in patients with lupus erythematosus as very rare cases of lupus erythematosus have been reported.

Effect of other medicinal products on terbinafine

The plasma clearance of terbinafine may be accelerated by drugs, which induce metabolism and may be inhibited by drugs, which inhibit cytochrome P450. Where co-administration of such agents is necessary, the dosage of Lamater tablets may need to be adjusted accordingly.

The following medicinal products may increase the effect or plasma concentration of terbinafine:

Cimetidine decreased the clearance of terbinafine by 30%.

Fluconazole increased the Cmax and AUC of terbinafine by 52% and 69% respectively, due to inhibition of both CYP2C9 and CYP3A4 enzymes. Similar increase in exposure may occur when other drugs which inhibit both CYP2C9 and CYP3A4 such as ketoconazole and amiodarone are concomitantly administered with terbinafine.

The following medicinal products may decrease the effect or plasma concentration of terbinafine:

Rifampicin increased the clearance of terbinafine by 100%.

Effect of terbinafine on other medicinal products:

Terbinafine may increase the effect or plasma concentration of the following medicinal products:

Caffeine: Terbinafine decreased the clearance of caffeine administered intravenously by 21%.

Compounds predominantly metabolised by CYP2D6:

In vitro and in vivo studies have shown that terbinafine inhibits the CYP2D6-mediated metabolism. This finding may be of clinical relevance for patients receiving compounds predominantly metabolised by this enzyme, e.g. certain members of the following drug classes, such as tricyclic antidepressants (TCAs), b-blockers, selective serotonin reuptake inhibitors (SSRIs), antiarrhythmics (including class 1A, 1B and 1C) and monoamine oxidase inhibitors (MAOIs) Type B, especially if they also have a narrow therapeutic window (see section 4.4).

Terbinafine decreased the clearance of desipramine by 82%.

‘In studies in healthy subjects characterized as extensive metabolisers of dextromethorphan (antitussive drug and CYP2D6 probe substrate), terbinafine increased the dextromethorphan/dextrorphan metabolic ratio in urine by 16- to 97-fold on average. Thus, terbinafine may convert extensive CYP2D6 metabolisers (genotype) to poor metaboliser status (phenotype).’

Information on other drug concomitantly used with terbinafine resulting in no or negligible interactions:

Studies undertaken in vitro and in healthy volunteers suggest that terbinafine shows negligible potential to inhibit or induce the clearance of most drugs that are metabolized via other cytochrome P450 enzymes (e.g. tolbutamine, terfenadine, triazolam, oral contraceptives) with exception of those metabolised through CYP2D6 (see below).

Terbinafine does not interfere with the clearance of antipyrine or digoxin.

There was no effect of terbinafine on the pharmacokinetics of fluconazole.Further there was no clinically relevant interaction between terbinafine and the potential comedications cotromixazole (trimethoprim and sulfamethoxazole), zidovudine or theophylline.

Some cases of menstrual disturbance (breakthrough bleeding and irregular cycle) have been reported in patients taking Terbinafine concomitantly with oral contraceptives, although the incidence of these disorders remains within the background incidence of patients taking oral contraceptives alone.

Terbinafine may decrease the effect or plasma concentration of the following medicinal products: Terbinafine increased the clearance of ciclosporin by 15%.

Rare cases of changes in International Normalised Ratio (INR) and/orprothrombin time have been reported in patients receiving terbinafineconcomitantly with warfarin.

Pregnancy

Foetal toxicity and fertility studies in animals suggest no adverse effects.

Since clinical experience in pregnant women is very limited, terbinafine should not be administered during pregnancy, unless clinical condition of the woman requires treatment with oral terbinafine and the potential benefits for the mother outweigh any potential risks for the foetus.

Breast-feeding

Terbinafine is excreted in breast milk and therefore mothers should not receive terbinafine treatment whilst breast-feeding.

Fertility

Foetal toxicity and fertility studies in animals suggest no adverse effects.

No studies on the effects of terbinafine tablets treatment on the ability to drive and use machines have been performed. Patients who experience dizziness as an undesirable effect should avoid driving vehicles or using machines.

Side effects are usually mild to moderate, and transient. The following adverse reactions have been observed in the clinical trials or during post marketing experience.

Adverse reactions are ranked under headings of frequency, using the following convention: very common (≥1/10); common (≥1/100, < 1/10); uncommon (≥1/1,000, < 1/100); rare (≥1/10,000, < 1/1,000;); very rare ( < 1/10,000), including isolated reports.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; e-mail: medsafety@hpra.ie.

A few cases of overdose (up to 5g) have been reported, giving rise to headache, nausea, upper abdominal pain and dizziness. The recommended treatment of overdosage consists in eliminating the drug, primarily by the administration of activated charcoal, and giving symptomatic supportive therapy if needed.

Pharmacotherapeutic group: Oral antifungal agent (ATC code D01B A02)

Mechanism of action

Terbinafine is an allylamine which has a broad spectrum of antifungal activity. At low concentrations terbinafine is fungicidal against dermatophytes, moulds and certain dimorphic fungi. The activity versus yeasts is fungicidal or fungistatic depending on the species.

Terbinafine interferes specifically with fungal sterol biosynthesis at an early step. This leads to a deficiency in ergosterol and to an intracellular accumulation of squalene, resulting in fungal cell death. Terbinafine acts by inhibition of squalene epoxidase in the fungal cell membrane.

The enzyme squalene epoxidase is not linked to the cytochrome P450 system. Terbinafine does not influence the metabolism of hormones or other drugs.

When given orally, the drug concentrates in skin at levels associated with fungicidal activity.

Absorption

Following oral administration, terbinafine is well absorbed (>70%) and the absolute bioavailability of terbinafine from Lamater tablets as a result of first-pass metabolism is approximately 50 %. A single oral dose of 250mg terbinafine resulted in a mean peak plasma concentrations of 1.3 microgram/ml within 1.5 hours of administration. Plasma concentrations decline in a triphasic manor, with a terminal half-life of 16.5 days. At 28 days, when around 70% steady state levels have been achieved, peak concentrations of terbinafine was on average 25% higher and plasma AUC increased by a factor of 2.3 when compared to single dose administration.From the increase in plasma AUC an effective half-life of approximately 30 hours can be calculated. The bioavailability of terbinafine is moderately affected by food (increase in the AUC of less than 20%), but not sufficiently to require dose adjustments.

Distribution

Terbinafine binds strongly to plasma proteins. It rapidly diffuses through the dermis and concentrates in the lipophilic stratum corneum.

Terbinafine is also secreted in sebum, thus achieving high concentrations in hair follicles, hair and sebum rich skins. There is also evidence that terbinafine is distributed into the nail plate within the first few weeks of commencing therapy.

Biotransformation

Terbinafine is metabolised rapidly and extensively by at least seven CYP isoenzymes with major contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8 and CYP2C19. Biotransformation results in metabolites with no antifungal activity, which are excreted predominantly in the urine.

Elimination

No clinically relevant age-dependent changes in pharmacokinetics have been observed. Single dose pharmacokinetics studies in patients with renal impairment (creatinine clearance < 50 mL/min) or with pre-existing liver disease have shown that the clearance of Terbinafine may be reduced by about 50%.

In long-term studies (up to one year) in rats and dogs no marked toxic effects were seen in either species up to oral doses of about 100mg/kg a day. At high oral doses, the liver and possibly also the kidneys were identified as potential target organs.

Carcinogenesis and mutagenesis

In a two-year oral carcinogenicity study in mice, no neoplastic or other abnormal findings attributable to treatment were made up to doses of 130 (males) and 156 (females) mg/kg a day. In a two-year oral carcinogenicity study in rats, an increased incidence of liver tumours was observed in males at the highest dosage level of 69mg/kg a day. The changes which may be associated with peroxisome proliferation have been shown to be species-specific since they were not seen in the carcinogenicity study in mice, dogs or monkeys.

During high-dose studies in monkeys, refractile irregularities were observed in the retina at the higher doses (non-toxic effect level 50mg/kg). These irregularities were associated with the presence of a terbinafine metabolite in ocular tissue and disappeared after drug discontinuation. They were not associated with histological changes.

A standard battery of in vitro and in vivo genotoxicity tests revealed no evidence of mutagenic or clastogenic potential.

Fertility and reproductive toxicity

No adverse effects on fertility or other reproduction parameters were observed in studies in rats or rabbits.

Microcrystalline cellulose

Colloidal silica anhydrous

Hypromellose

Sodium starch glycollate Type A

Magnesium stearate

Not applicable.

3 years

Keep the blister in the outer carton in order to protect from light.

PVC/PVDC/aluminium foil opaque blister packs containing 7, 14, 28, 30 or 100^* tablets.

^*Not all pack sizes may be marketed

Wockhardt UK Limited

Ash Road North

Wrexham

LL13 9UF

United Kingdom

Date of First Authorisation: 16th May 2008.

October 2017

Not applicable.